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Background: It is challenging for outcome assessors to remain blinded during outcome assessment in trials with prospective randomized open blinded endpoint (PROBE) design. If assessors are able to guess the correct treatment allocation more often than expected based on chance, the assessors may have been not properly blinded. Aims: We aimed to assess blinding of outcome assessors in a stroke trial with PROBE design and its association with outcome. Methods: We used data of the Interventional Management of Stroke (IMS) III trial. The modified Rankin Scale (mRS) at 90 days was assessed by local assessors who were unaware of treatment allocation. To assess success of blinding, each assessor was asked to guess the patient’s treatment allocation. We assessed whether the percentage of correct guesses was higher than chance (i.e. 50%). The association between correctly guessed treatment allocation and the mRS at 90 days was analyzed with ordinal logistic regression stratified by treatment allocation. We tested for interaction of correctly versus incorrectly guessed treatment allocation with actual treatment allocation on the mRS. Patients with missing data on guessed treatment allocation and patients who died prior to 90-day assessment were excluded. Results: In total, 459 patients were included in this study. The assessors guessed the correct treatment allocation significantly more often than expected (267/459, 58.2%, one-sided p = 0.0003). Correctly guessed treatment allocations were associated with better mRS scores in the intervention group (common odds ratio (cOR): 2.28, 95% confidence interval (CI): 1.50–3.48) and with worse mRS scores in the control group (cOR: 0.47, 95% CI: 0.27–0.83) (pinteraction Conclusions: Assessors may not always be truly blinded for treatment allocation in clinical trials, and their guesses may be associated with outcome. Although causality between the assessors’ guess and patient outcome cannot be determined, future trials with subjective outcome should make efforts to ensure blinding and should report their blinding method and the success of blinding like the IMS III trial. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT00359424.

A systematic experimental study is conducted on floating field rings (FFR) incorporated into 4H-SiC junction barrier Schottky (JBS) diodes across four voltage ratings 650, 1200, 1700 and 3300V, in pursuit of highly efficient FFR designs. 30 designs of FFR in 3 categories are studied for each voltage rating, and the measured breakdown voltage (Vbr) of JBS divided by ring system width (W) is taken as the figure of merit (FOM) of each design. The influence of ring spacing, ring width and number of rings on Vbr is studied in detail. It is found that the initial ring spacing (S1) is critical in determining the highest Vbr achievable by a certain design, and its optimum value increases as voltage rating increases. TCAD simulation verifies the importance of S1. For designs with a small ring system width, subsequent ring spacing can also become important. Ring width does not have a definitive effect, and Vbr saturates beyond a certain ring number. The design with the highest Vbr may not render the highest FOM. Even style designs with appropriate ring spacings can be advantageous likely due to less susceptibility to variation of field oxide charge, and more tolerance to fabrication error, as well as ease of design.

The loggerhead sea turtle (Caretta caretta), has the widest distribution among sea turtle species in the Mediterranean, requiring regional and international collaborations in addition to local efforts to better inform conservation actions. Molecular techniques are powerful tools for the assessment of population dynamics at large scales, especially in determining the connectivity among different nesting and foraging sites, and genetic diversity. In this study, a large sample was collected synchronously in the nesting areas located in the north, south and eastern Mediterranean. Recently confirmed nesting sites from Albania and other nesting sites represented by lower sample sizes were also included in order to better assess the genetic composition of the region's rookeries. Samples from 698 individuals were collected and the longer (815 bp) mtDNA D-loop fragment of these samples was sequenced. We recorded 15 haplotypes, three of which were novel. In addition, our results show that some haplotypes considered of Atlantic origin, have a wider dispersal in the Mediterranean than previously thought, albeit with low levels of representation. Our results contribute to determining the likely origin of haplotypes that were previously only recorded from foraging sites. They highlight the utility of broad-scale sampling, with increased sample sizes and the longer mtDNA sequence to determine genetic diversity and connectivity. This study also demonstrates the importance of continued monitoring for the contribution of Atlantic-origin haplotypes to the Mediterranean population and the effects of climate change on the resident Mediterranean population, which is expected to expand its geographical range for reproduction. This work is important for, mixed stock analyses (MSA) that seek to determine the natal regions of stranded or accidentally caught sea turtles and those purposefully obtained from foraging sites. In doing so biogeographic linkages between areas of the Mediterranean can be elucidated for conservation purposes.

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation^{1,2}. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole^3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of 8.4_{-1.1}^{+0.5} Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow., 50 pages, 18 figures, 3 tables, author's version of the paper published in Nature

Background: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. Methods: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. Results: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0–2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to Conclusions: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

There is a reliance on surgeons to provide advice to patients regarding safe return to driving following hip or knee arthroplasty. Concerns arise that misinformation may place the surgeon in a position of potential legal implication. The purpose of this article is to inform surgeons of their role in accordance with advice from insurance companies and transport regulatory bodies.We sought the stipulations from 5 of the top 10 insurance companies in the United States, Canada, Australia, and the United Kingdom and the transport regulatory body of each country with regards to guidelines on driving after arthroplasty surgery.The transport regulatory bodies of the countries evaluated do not provide explicit recommendations regarding return to driving after hip or knee arthroplasty and place the responsibility of determining fitness to drive on the treating doctor. Insurance company policies do not contain specifics pertaining to driving after surgery and in most cases defer to the treating doctor to make this decision. Guidelines are available in Canada and America with suggested timeframes on return to driving following arthroplasty surgery.Advice regarding return to driving following hip or knee arthroplasty should be individualized for each patient; ultimately the patient must feel safe to drive knowing that they have a legal responsibility to remain in control of the vehicle at all times. It is recommended that surgeons document any discussion regarding return to driving and should not feel that they are contravening any prescriptive regulation by allowing driving when appropriate.

We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

Background and ObjectivesThe EuroQol Group 5-Dimension Self-Reported Questionnaire (EQ-5D) is a well-established instrument to assess quality of life and generates generic utility values for health states reported by patients, derived from assessments by the general public. We hypothesized that language problems and other nonmotor deficits are not captured as well as motor deficits by this system. We aimed to quantify the association between disabling neurologic deficits and the EQ-5D dimension scores and the utility score in patients with ischemic stroke.MethodsWe used data of the Interventional Management of Stroke III trial. Missing data were imputed by multiple imputation. The association between neurologic deficits (individual NIH Stroke Scale [NIHSS] item scores) and the EQ-5D-3L (5 three-level dimension scores and utility score) at 90 days was assessed with ordinal logistic regression and Tobit regression, respectively. The explained variance of each model was estimated with Nagelkerke pseudo-R2or R2.ResultsIn total, 525 surviving patients were included. Complete data on both the NIHSS and EQ-5D were available for 481/525 (91.6%) patients. At 90 days, 161/491 (32.8%) patients had aphasia and 226/491 (46.0%) patients had paresis of at least 1 limb. Limb paresis, facial palsy, sensory loss, and dysarthria explained most of the variance in all EQ-5D dimension scores and the utility score. In the utility score, 8.9% of the variance was explained by neglect, 10.0% by aphasia, 10.8% by hemianopia, and 17.5%–24.1% by limb paresis.DiscussionThe impact of neurologic deficits on the EQ-5D in patients with ischemic stroke is mostly due to limb paresis, while the EQ-5D is less sensitive to other nonmotor deficits such as hemianopia, aphasia, and neglect. This may lead to overestimation of quality of life and, consequently, underestimation of the (cost-)effectiveness of treatments and interventions.Trial Registration InformationClinicalTrials.gov. Unique identifier:NCT00359424.

Background: Heterozygous hotspot mutations in the RNA splicing factor SF3B1, occur in 3% of unselected breast cancers and are associated with oestrogen receptor (ER+) breast cancer (BC) where they are enriched in metastatic disease and are associated with a poor clinical outcome. SF3B1 mutations drive distinct signatures of alternative splicing through cryptic 3’ splice site selection leading to global transcriptomic and proteomic changes. The functional consequences of the mis-splicing events and resultant genetic vulnerabilities are poorly understood and precision medicine approaches that exploit these characteristics are not clinically available (Table 1). Methods: To understand the role of SF3B1 mutations in ER+ BC, we generated a series of SF3B1 mutant (SF3B1MUT) isogenic cell lines which were characterised using RNA-sequencing and high content mass-spectrometry proteomic profiling. SF3B1 interactome analysis was also performed using immunoprecipitation of SF3B1 followed by mass-spectrometry. The molecular consequences of aberrant splicing were investigated using a targeted screening approach of 280 genes predicted to be alternatively spliced in SF3B1MUT BC, while high-throughput drug screens were used to identify novel therapeutic options for patients with SF3B1MUT breast cancer using isogenic cells. Hits were validated in vitro and in vivo using cell line and patient derived xenografts. Results: Transcriptomic and proteomic profiling of SF3B1MUT cells identified global alternative 3’ splice site selection and subsequent proteomic changes induced by the mutations. Investigation of the SF3B1K700E interactome identified an enrichment of SF3B1K700E binding with ER, aberrant splicing of ER target genes, global rewiring of ER chromatin binding and resistance to endocrine therapy. Silencing of the aberrantly spliced candidate genes PPIH, TRIM37, HIGD1A, BRD9, and PHKG2 significantly enhanced the growth of the SF3B1 mutant cells, suggestive of a dose dependent tumour suppressive effect. Through synthetic-lethal drug screens we found that SF3B1MUT cells are selectively sensitive to PARP inhibitors. SF3B1MUT cells display a defective response to PARPi induced replication stress. Mechanistically, this occurs via defective ATR signalling in SF3B1MUT cells, which upon PARPi exposure leads to increased replication origin firing and loss of pChk1 (S317) induction. The resultant replication stress leads to failure to resolve DNA replication intermediates via the endonuclease MUS81 and cell cycle stalling at the G2/M checkpoint. These defects can be further targeted by ATM, CDK7 or FACT inhibition, when used in combination with PARPi treatment. This SF3B1MUT selective PARPi sensitivity is preserved across multiple cell lines and patient derived tumour models. In vivo, PARPi produce profound anti-tumour effects in multiple SF3B1MUT cancer models and eliminate distant metastases. Conclusions: Our integrative analysis reveals mechanistic insight into the role of SF3B1 mutations in endocrine therapy response in ER+ breast cancers, where altered SF3B1 induces ER-transcriptional re-programming. We further identified a robust synthetic-lethal relationship of mutant SF3B1 with PARP inhibition that is caused by a defective response to PARPi induced replication stress. Furthermore, we identified several potential selective combination strategies together with PARPi that are selective for SF3B1MUT cells. Together, these data provide the pre-clinical and mechanistic rationale for assessing already-approved PARPi in a biomarker-defined subset of advanced ER+ BC. Table 1. Identified potential therapies for SF3B1 mutant cancers from this study and the literature Citation Format: Phil Bland, Harry Saville, Abigail Read, Patty Wai, Gareth Muirhead, Lucinda Curnow, Jadwiga Nieminuszczy, Nivedita Ravindran, Marie John, Somaieh Hedayat, Holly Barker, James Wright, Lu Yu, Ioanna Mavrommati, Barrie Peck, Mark Allen, Patrycja Gazinska, Helen Pemberton, Aditi Gulati, Sarah Nash, Farzana Noor, Naomi Guppy, Ioannis Roxanis, Samantha Barlow, Helen Kalirai, Sarah Coupland, Ronan Broderick, Samar Alsafadi, Alexandre Houy, Marc-Henri Stern, Stephen Pettit, Jyoti Choudhary, Syed Haider, Wojciech Niedzwiedz, Christopher Lord, Rachael Natrajan. Mutations in the RNA Splicing Factor SF3B1 drive endocrine therapy resistance and confer a targetable replication stress response defect through PARP inhibition. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-05.

What is this summary about? In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non–small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). What happened in the study? Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. What were the results? Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. What do the results of the study mean? Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 ( ClinicalTrials.gov )

Purpose:Neoadjuvant anti–PD-1 therapy has shown promise for resectable non–small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti–PD-1 in any cancer type.Patients and Methods:Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I–IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated.Results:With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15–2.44] and HR, 0.36 (95% CI, 0.07–1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died.Conclusions:Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

The Eastern Health Clinical Biochemistry Laboratories cater to the province of Newfoundland and Labrador. Over the last ten years, a significant increase in annual expenses on quality control material and calibrator purchases was observed. Two major Clinical Chemistry Laboratories at the Health Sciences Centre (HSC) and St. Clare's Mercy Hospital (STC), St. John's, work as referral centers for the province. The study's design was based on the Six Sigma DMAIC (Define, Measure, Analyze, Improve, and Control) process and involved tests performed on ten automated Abbott Clinical Chemistry (CC) and Immunoassay (IA) analyzers. The cost of purchasing the QC material from Bio-Rad and Randox had increased due to defective QC and analyzer test assignment process design. The processes were modified. An Individualized Quality Control Plan (IQCP) was developed.Modification in quality control processes helped in bringing down the cost and usage of both QC and calibrators. The cost and usage of individual control material were reduced by 25 to 52% depending on the type of quality control. Total annual expenditure on the purchase of different QC materials before modification was estimated as CAD 346,395(2019) which was reduced to CAD 255,267 with annual savings of 91,128 CAD (26%) after modification (2020). The average usage reduction for various calibrators was 40% with the highest reduction in the use of urine calibrators. The annual cost of calibrators was reduced from CAD 30,568.42 (2019-20) to CAD 17,517 (2020-21) with the saving of approximately 13,051 Canadian dollars (43 %) for the laboratory.There is a constant compulsion in every industry to manage costs. Implementation of Lean and Six Sigma methodology in removing Muda of high costs in a Clinical Chemistry Laboratory is the most warranted strategy in developing a cost-effective laboratory framework.

There is a growing interest in the estimation of the number of unseen features, mostly driven by biological applications. A recent work brought out a peculiar property of the popular completely random measures (CRMs) as prior models in Bayesian nonparametric (BNP) inference for the unseen-features problem: for fixed prior’s parameters, they all lead to a Poisson posterior distribution for the number of unseen features, which depends on the sampling information only through the sample size. CRMs are thus not a flexible prior model for the unseen-features problem and, while the Poisson posterior distribution may be appealing for analytical tractability and ease of interpretability, its independence from the sampling information makes the BNP approach a questionable oversimplification, with posterior inferences being completely determined by the estimation of unknown prior’s parameters. In this article, we introduce the stable-Beta scaled process (SB-SP) prior, and we show that it allows to enrich the posterior distribution of the number of unseen features arising under CRM priors, while maintaining its analytical tractability and interpretability. That is, the SB-SP prior leads to a negative Binomial posterior distribution, which depends on the sampling information through the sample size and the number of distinct features, with corresponding estimates being simple, linear in the sampling information and computationally efficient. We apply our BNP approach to synthetic data and to real cancer genomic data, showing that: (i) it outperforms the most popular parametric and nonparametric competitors in terms of estimation accuracy; (ii) it provides improved coverage for the estimation with respect to a BNP approach under CRM priors. Supplementary materials for this article are available online.

Background: Assisted falls occur when staff try to minimize the impact of falls by slowing a patient’s descent. Assisting a patient fall may decrease patient injury risk, but biomechanical risk of injury to staff has not been evaluated. Assisted falls virtual reality (VR) simulations were conducted to examine staff low back injury risk during common assisted falls scenarios. Methods: VR simulations of a toilet to wheelchair transfer were developed with a male patient avatar for three assisted falls scenarios: standing up from toilet, sitting down on wheelchair, and ambulation. Patient avatar weight was modified to reflect normal, underweight, and overweight adult patients. The average spinal compression force at L5/S1 was calculated for each participant with five trials per three scenarios while utilizing physical ergonomic techniques and compared to the safe spinal compression limit of 3,400 Newtons (N). Findings: Six staff participants completed 90 VR simulations in total. The average calculated spinal compression force ranged from 7,132 N to 27,901 N. All participant trials exceeded the safe spinal compression limit of 3,400 N for every assisted falls scenario and avatar weight despite application of ergonomic techniques including wide stance, knees bent, and backs straight. Conclusions/Application to Practice: Staff are at risk for low back injury if they assist falls regardless of the adult patient weight and application of ergonomic techniques. Safer alternatives like the implementation of mobility screening tools and safe patient handling and mobility technology are needed to help prevent assisted falls to decrease injury risk to both patients and staff.

Background Age is a poor predictor of postoperative outcomes in breast reconstruction necessitating new methods for risk-stratifying patients preoperatively. The 5-item modified frailty index (mFI-5) is a validated measure of frailty which assesses patients' global health. The purpose of this study was to compare the effectiveness of mFI-5 and age as independent predictors of 30-day postoperative complications following autologous breast reconstruction. Methods Patients who underwent autologous breast reconstruction between 2005 and 2019 were identified from the American College of Surgeons National Surgical Quality Improvement Program. Patients were stratified based on presence of major, minor, both minor and major, and no complications. Univariate and multivariate logistic regression were performed to determine the predictive power of mFI-5, age, and other preoperative risk factors for development of minor and major 30-day postoperative complications in all patients and stratified by flap type. Results A total of 25,215 patients were included: 20,366 (80.8%) had no complications, 2,009 (8.0%) had minor complications, 1,531 (6.1%) had major complications, and 1,309 (5.2%) had both minor and major complications. Multivariate regression demonstrated age was not a predictor of minor (odds ratio [OR]: 1.0, p = 0.045), major (OR: 1.0, p = 0.367), or both minor and major (OR: 1.0, p = 0.908) postoperative complications. mFI-5 was a significant predictor of minor complications for mFI-5 scores 1 (OR: 1.3, p Conclusion Compared with age, mFI-5 scores were better predictors of 30-day postoperative complications following autologous breast reconstruction regardless of flap type. Additionally, higher mFI-5 scores were associated with increased odds of minor and major complications. Our findings indicate that reconstructive breast surgeons should consider using the mFI-5 in lieu of age to risk-stratify patients prior to autologous breast reconstruction surgery.

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes during a median of 3.2 years. Extended follow-up for mortality is ongoing. Methods: ISCHEMIA participants were randomized to an initial invasive strategy added to guideline-directed medical therapy or a conservative strategy. Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and noncardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models, and Bayesian methods. Undetermined deaths were classified as cardiovascular as prespecified in the trial protocol. Results: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23% women, 16% Hispanic, 4% Black, 42% with diabetes, and median ejection fraction 0.60. A total of 557 deaths accrued during a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 noncardiovascular deaths, and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate, 12.7% in invasive strategy, 13.4% in conservative strategy; adjusted hazard ratio, 1.00 [95% CI, 0.85–1.18]). There was a lower 7-year rate cardiovascular mortality (6.4% versus 8.6%; adjusted hazard ratio, 0.78 [95% CI, 0.63–0.96]) with an initial invasive strategy but a higher 7-year rate of noncardiovascular mortality (5.6% versus 4.4%; adjusted hazard ratio, 1.44 [95% CI, 1.08–1.91]) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. Conclusions: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of noncardiovascular mortality with an initial invasive strategy during a median follow-up of 5.7 years. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04894877.

This article looks briefly at the significance of the triskele and swastika as sun-symbols in general and their long association with Insular Celtic traditions, and with the Isle of Man in particular, as well as the association of the triskele and other traditions with Manannán mac Lir (Manannan Beg mac y Leirr in Man) and with Tynwald, the Manx parliament, in Manx tradition over time.

Background: Adjuvant chemotherapy has been an integral component of breast cancer care for decades. Advances in supportive care have been made, but despite this, infective complications of therapy remain a significant toxicity concern. Case Presentation: A premenopausal patient presented to the emergency department during the third wave of the Covid-19 pandemic with sepsis after a second course of adjuvant docetaxel-cyclophosphamide chemotherapy. Overnight she developed tetraplegia. An urgent MRI cervical spine revealed a pre-vertebral, vertebral, and epidural abscess. This was treated with an emergency C4-C7 posterior cervical laminectomy and decompression. Her inpatient care involved a protracted ICU admission followed by rehabilitation. She remains tetraplegic and requires continued inpatient care over a year after presentation. Restricted pandemic-related hospital visiting has compounded the impact of her illness. Conclusion: Infective complications of adjuvant breast cancer chemotherapy remain an issue despite advances in supportive care. This case highlights the devastating, life-altering impact that these complications can have as emphasized by the inclusion of the patient’s perspective.

Physical activity levels are low in cancer survivors. Remotely delivered programs which harness wearable technology may potentially be beneficial. To evaluate the feasibility and preliminary efficacy of a remotely delivered, physical activity intervention which harnessed wearable technology. This single arm pre-post longitudinal study included cancer survivors who had completed treatment in the preceding 3 years. Participants were supplied with a Fitbit One® or Flex® for 12 weeks. Physical activity goals were discussed during support phone calls. Outcome measures, assessed at baseline (T1), 12 weeks (T2), and 24 weeks (T3), included feasibility (recruitment, adherence, safety, acceptability) and efficacy [physical activity (Godin leisure time Index, ActiGraph GT3X+), quality of life (functional assessment of cancer therapy – general, short form 36 physical functioning component), functional capacity (six-minute walk test)]. Forty-five participants completed T1 assessments (10 males, 35 females). Thirty-nine (86.6%) of those underwent assessment at T2 and 31 (68.8%) at T3. The intervention was perceived positively with no adverse effects. There were increases in functional capacity (six-minute walk test, p = .002) between T1-T3, an increase in quality of life [short form 36 physical functioning measure (p = .0035), functional assessment of cancer total score (p = .02)] and self-report physical activity levels (p = .000123) between T1-T2, although effect sizes were generally low (d = 0.180 to d = 0.418). Objectively measured physical activity did not change. A physical activity intervention including wearable technology was safe, feasible, and well received by cancer survivors. An intervention based on this proof of concept should be followed up in further studies.

Eine diplomatische Transkription des von Rhŷs zusammengefassten Tagebuches seiner Aufenthalte auf der Insel Man (1886-1893) zur Erhebung von Beispielen des gesprochenen Manx-Gälischen von 88 vorhandenen Muttersprachlerinnen und Muttersprachlern aus allen Gebieten der Insel.

Patients with generalized myasthenia gravis (gMG) experience functional impairment due to MG symptoms. This study aimed to assess, from the patient perspective, the symptoms, impacts, and treatment goals of individuals diagnosed with gMG.Semi-structured, in-depth concept-elicitation interviews were conducted with 28 individuals diagnosed with gMG in the United States.Participants reported gMG symptoms that affected many body regions and functions, with an average of 16 symptoms per participant. The most frequently reported symptoms were eyelid drooping (93%), physical fatigue (89%), symptoms affecting the legs (82%), difficulty breathing (82%), and difficulty holding head up (82%). Nearly all participants (96%) reported fluctuations in symptoms and severity. Participants' most bothersome symptoms were blurry/double vision (43%), breathing difficulties (36%), all-over fatigue (36%), and swallowing problems (29%). Impacts on physical functioning included an inability to participate in hobbies/sports, need for increased planning, and difficulties performing activities of daily living. All participants reported emotional impacts and impacts on their work and finances. Their treatment goals included reduced fatigue and weakness, improved symptom stability, and minimization of the impact of symptoms, in particular the emotional impact.The fluctuating and unpredictable nature of gMG symptoms was found to have a substantial impact on patients' emotional, social, and economic well-being. Participants' goals for symptom management suggest that greater focus is needed to help them quickly resume a normal lifestyle by achieving symptom stability. Impacts of fluctuating and unpredictable symptoms are difficult to measure, but it is important to consider symptom fluctuation as well as ongoing symptomatology when making treatment decisions, and to recognize the impact of uncontrolled symptoms on patients, their partners/caregivers, and family/friends. These factors are often not reflected in burden/cost-of-illness studies.The aim of this study was to understand—from the patient’s point of view—the range of generalized myasthenia gravis (gMG) symptoms that they experience, which symptoms bother them most, and which symptoms have the greatest impact on everyday life, as well as patients’ treatment goals. Researchers asked these questions in one-on-one interviews with 28 people in the US who have gMG. Study participants reported living with symptoms that come and go, and are sometimes severe, making it difficult to lead a normal life. The most frequently reported symptoms were eyelid drooping (reported by 93% of study participants), physical fatigue (89%), symptoms affecting the legs (82%), difficulty breathing (82%), and difficulty holding head up (82%). The symptoms that bothered patients most were difficulties with vision (43%), problems breathing (36%), all-over fatigue (36%), and trouble swallowing (29%). Participants reported that gMG symptoms affected physical functioning, making it hard to participate in hobbies/sports, increasing the amount of planning needed to conduct their daily lives, and hindering their ability to do day-to-day activities (like driving, eating, and bathing). All participants reported that they were affected emotionally, and that the symptoms of gMG impacted their ability to work and their financial well-being. Participants’ treatment goals included reducing fatigue and weakness, making symptoms more stable, and reducing the impact of symptoms, particularly emotional impacts. These responses reveal the extensive effects of gMG symptoms on patients’ daily lives and highlight that symptom stability is especially important to people with gMG.

The Event Horizon Telescope (EHT) has led to the first images of a supermassive black hole, revealing the central compact objects in the elliptical galaxy M87 and the Milky Way. Proposed upgrades to this array through the next-generation EHT (ngEHT) program would sharply improve the angular resolution, dynamic range, and temporal coverage of the existing EHT observations. These improvements will uniquely enable a wealth of transformative new discoveries related to black hole science, extending from event-horizon-scale studies of strong gravity to studies of explosive transients to the cosmological growth and influence of supermassive black holes. Here, we present the key science goals for the ngEHT and their associated instrument requirements, both of which have been formulated through a multi-year international effort involving hundreds of scientists worldwide., 32 pages, 11 figures, accepted for publication in a special issue of Galaxies on the ngEHT (https://www.mdpi.com/journal/galaxies/special_issues/ngEHT_blackholes)

Radical S-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo•) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe–C5′-adenosyl bond. Regioselective reductive cleavage of the SAM S–C5′ bond produces 5′-dAdo• to form Ω, with the regioselectivity originating in the Jahn–Teller effect. Ω liberates the free 5′-dAdo• as the catalytically active intermediate through homolysis of the Fe–C5′ bond, in analogy to Co–C5′ bond homolysis in B12, which was once viewed as biology's choice of radical generator. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Radical S-adenosyl-l-methionine (SAM) enzymes employ a [4Fe–4S] cluster and SAM to initiate diverse radical reactions via either H-atom abstraction or substrate adenosylation. Here we use freeze-quench techniques together with electron paramagnetic resonance (EPR) spectroscopy to provide snapshots of the reaction pathway in an adenosylation reaction catalyzed by the radical SAM enzyme pyruvate formate-lyase activating enzyme on a peptide substrate containing a dehydroalanine residue in place of the target glycine. The reaction proceeds via the initial formation of the organometallic intermediate Ω, as evidenced by the characteristic EPR signal with g(∥) = 2.035 and g(⊥) = 2.004 observed when the reaction is freeze-quenched at 500 ms. Thermal annealing of frozen Ω converts it into a second paramagnetic species centered at g(iso) = 2.004; this second species was generated directly using freeze-quench at intermediate times (~8 s) and unequivocally identified via isotopic labeling and EPR spectroscopy as the tertiary peptide radical resulting from adenosylation of the peptide substrate. An additional paramagnetic species observed in samples quenched at intermediate times was revealed through thermal annealing while frozen and spectral subtraction as the SAM-derived 5′-deoxyadenosyl radical (5′-dAdo•). The time course of the 5′-dAdo• and tertiary peptide radical EPR signals reveals that the former generates the latter. These results thus support a mechanism in which Ω liberates 5′-dAdo• by Fe–C5′ bond homolysis, and the 5′-dAdo• attacks the dehydroalanine residue of the peptide substrate to form the adenosylated peptide radical species. The results thus provide a picture of a catalytically competent 5′-dAdo• intermediate trapped just prior to reaction with the substrate.

Transnational solidarity and comprehensive critiques of colonial legacies and patriarchal systems united the cultural responses created during the campaigns for reproductive justice in Ireland and Chile in 2018. This article considers the performance piece ‘Abortistas’ by the Yeguada Latinoamericana in Chile and the poem ‘Granuaile’ by Róisín Kelly in Ireland. Taking a decolonial feminist approach, this comparative study explores the interstices of art form and geopolitically distinct territories to examine how the creative practitioners' discursive construction of insurgent bodies aids critique of the lived experiences of women and pregnant people under the restrictive reproductive laws of both countries.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related death. For patients who develop metastatic disease, tissue-based and circulating-tumor–based molecular and genomic biomarkers have emerged as a means of improving outcomes through the application of precision medicine. However, the benefit is limited to a minority of patients. An additional approach to further characterize the biology of advanced prostate cancer is through the use of phenotypic precision medicine, or the identification and targeting of phenotypic features of an individual patient’s cancer. In this review article, we will discuss the background, potential clinical benefits, and limitations of genomic and phenotypic precision medicine in prostate cancer. We will also highlight how the emergence of image-based phenotypic medicine may lead to greater characterization of advanced prostate cancer disease burden and more individualized treatment approaches in patients.